Kinetic resolution of oxime esters with lipases - Synthesis of enantiomerically enriched building blocks with quaternary carbon centers and formal total synthesis of perhydro histrionicotoxin

Article abstract of DOI:10.1139/v02-097

Enantiomerically enriched oximes bearing stereogenic quaternary carbon centers can be obtained by lipase-catalyzed kinetic resolution of oxime esters. Substrate specificity, solvent effects, and the use of different lipases are discussed. Kinetic resolution of butyrylated oximes by lipase PS in the presence of n-butanol gave the best ee-values of both the saponified oxime and the residual oxime ester. Subsequent stereospecific Beckmann rearrangement of an enantiomerically enriched oxime provided lactams, which could be employed for the synthesis of optically active perhydro histrionicotoxin.

Full text of DOI:10.1139/v02-097

686
Kinetic resolution of oxime esters with lipases —
synthesis of enantiomerically enriched building
blocks with quaternary carbon centers and formal
total synthesis of perhydro histrionicotoxin
Nicole Diedrichs, Ralf Krelaus, Ina Gedrath, and Bernhard Westermann
Abstract: Enantiomerically enriched oximes bearing stereogenic quaternary carbon centers can be obtained by lipase-
catalyzed kinetic resolution of oxime esters. Substrate specificity, solvent effects, and the use of different lipases are
discussed. Kinetic resolution of butyrylated oximes by lipase PS in the presence of n-butanol gave the best ee-values of
both the saponified oxime and the residual oxime ester. Subsequent stereospecific Beckmann rearrangement of an
enantiomerically enriched oxime provided lactams, which could be employed for the synthesis of optically active
perhydro histrionicotoxin.
Key words: oxime, lipase, kinetic resolution, Beckmann rearrangement, perhydro histrionicotoxin.
Résumé : Le dédoublement cinétique d’esters d’oximes catalysé par une lipase permet d’obtenir des oximes énantiomé-
riquement enrichies, portant des centres carbonés quaterneraires stéréogéniques. On discute de la stéréospécificité des
substrats, des effets de solvant et de l’utilisation de diverses lipases. Le dédoublement cinétique d’oximes portant un
groupe butyryle sous l’influence de la lipase PS, en présence de butanol, donne les meilleurs valeurs d’ee pour l’oxime
saponifiée et pour l’ester d’oxime résiduel. Une transposition de Beckmann stéréospécifique subséquente d’une oxime
énantiomériquement enrichi fournit des lactames qui peuvent être utilisés pour la synthèse de la perhydrohistrionico-
toxine optiquement active.
Mots clés : oxime, lipase, dédoublement cinétique, transposition de Beckmann, perhydrohistrionicotoxine.
[Traduit par la Rédaction] Diedrichs et al. 691
Introduction
Due to its stereospecificity, the synthesis of natural product
precursors 3 (spirocyclic framework of histrionicotoxins) or
products of pharmaceutical interest 4 (non-natural amino ac-
ids) via lactams 2 can be accomplished (Scheme 1). All ox-
imes employed bear a common stereogenic quaternary-
carbon center adjacent to the oxime functionality. Although
other methods to provide enantiomerically pure building blocks
possessing quaternary-carbon centers have been published,
there is still a need for widely applicable procedures (5).
Herein we describe a general method to obtain enantio-
merically enriched oximes 1 via kinetic resolution of
racemic oxime esters with lipase PS. In addition, the appli-
cation of these intermediates in the synthesis of the enantio-
merically pure spirocyclic framework of histrionicotoxin is
reported. The synthesis of non-natural amino acids has been
described elsewhere (6).
Enzymes are used in organic chemistry for their numerous
advantages as mild and easy-to-handle catalysts (1). Their
exquisite chemo-, regio-, and stereoselectivity has been dem-
onstrated numerous times. Most reported reactions are
hydrolytic reactions, e.g., lipase-catalyzed esterifications,
transesterifications, and saponifications of esters. In an over-
whelming number of studies, employment of irreversible
transacylating reagents has had a major impact in diversify-
ing the use of hydrolytic enzymes (2). In this context, oxime
esters have been used as irreversible acyl transfer agents,
sometimes exhibiting superior activity compared with their
anhydride or vinyl-derived congeners (3). Despite these ad-
vantages, the resolution of racemic oximes or oxime esters
have been studied infrequently (4).
Oximes 1 are involved in many different reactions, the
Beckmann rearrangement being one of the most prominent.
Results and discussion
Received 17 January 2002. Published on the NRC Research
Press Web site at http://canjchem.nrc.ca on 29 May 2002.
Synthesis of E-oximes
Racemic oximes (±)-1 can be obtained from alkylated b-
ketoesters (±)-5 by treatment with hydroxyl ammonium
chloride in pyridine–ethanol (Scheme 2) (6a). The reaction
is carried out at 0°C to afford almost exclusively the E-ox-
imes in quantitative yields (the ratio of E:Z stereoisomers is
always >50:1 as determined by GLC analysis). The E-con-
figuration of the oximes has been established by subsequent
Dedicated to my teacher and mentor J.B. Jones on the
occasion of his 65th birthday.
N. Diedrichs, R. Krelaus, I. Gedrath, and
B. Westermann.1 Department of Organic Chemistry,
33095 Paderborn, University of Paderborn, Germany.
1Corresponding author (e-mail: bw@fb13n.uni-paderborn.de).
Can. J. Chem. 80: 686–691 (2002)
DOI: 10.1139/V02-097
© 2002 NRC Canada

Diedrichs et al.
687
Table 1. Influence of the carboxylic acid moiety R> in oxime ester (±)-7a–11a.
ee-Value (%)a
Yield (%)b
Ester
R>
Reaction time (h)
(–)-Ester
(+)-Oxime
96
Oxime
7a
8a
9a
10a
11a
47
Fast
Fast
No reaction
130
CH3
92
94
90
ClCH2
CH3OCH2
(CH3)3C
C3H7
Unselective reaction
Unselective reaction
94
96
88
90
aDetermined by GLC (Hydrodex b-PM) and HPLC (Chiralcel OB-H).
bIsolated yields.
Scheme 1.
Scheme 2.
Scheme 3.
All enzyme catalyzed reactions reported in this publica-
tion have been monitored by GLC (cyclodextrin-modified
stationary phase for oximes) and HPLC (Daicel stationary
phases for oxime esters). Using these materials, base-line
separation of the racemic substrates was achieved in all
cases. The respective assignment of the absolute (S)- and
(R)-configurations of the quaternary stereogenic centers in
(+)-7a and (–)-1a were based on chemical correlation to
products obtained by PLE-catalyzed saponification of b-
ketoesters (±)-5 (7). The enantiomerically pure b-ketoesters
obtained by this method have been employed in the total
synthesis of the alkaloids (+)-nitramine and (–)-isonitramine.
Thus, the stereogenic center in (+)-7a is (S)-configured, and
in (–)-1a it is (R)-configured.
Beckmann rearrangements, which afforded lactams 2 as the
sole products in high yields. The isoxazolidinone (±)-6 is
formed in quantitative yield, if the reaction is carried out un-
der thermodynamic control (e.g., boiling chloroform).
Lipase-catalyzed kinetic resolution of oximes (±)-1
Lipase-catalyzed kinetic resolutions can be carried out in
two ways, either employing irreversible transacylating
agents like vinyl acetate in the presence of racemic oximes
or using racemic oxime esters in transesterification reac-
tions. In our initial experiments, the kinetic resolution of
oxime (±)-1a was carried out with lipase PS in the presence
of vinyl acetate (Scheme 3). Kinetic resolution was achieved
by stirring the oxime in diisopropyl ether with lipase PS.
While high selectivities (ee-values > 90%) were obtained,
the reactions took about one month. Optimization and
screening of various lipases showed no significant effect.
(The employed lipases were all of microbial origin:
Aspergillus niger, Candida antarctica, Candida cylindracea,
Mucor miehei, Pseudomonas cepacia, Pseudomonas
fluorescens and Mucor javanicus.). We therefore abandoned
this approach and envisioned carrying out kinetic resolution
reactions starting from the corresponding racemic oxime es-
ters (±)-7a and derivatives thereof.
Lipase-catalyzed kinetic resolution of oxime esters
To identify the best stereodifferentiation by the enzyme,
several carboxylic esters of the allylated oxime (±)-1a were
reacted in diisopropyl ether as solvent containing n-butanol.
The methoxy- and the chloro-substituted acetic acid deriva-
tives (±)-8a and (±)-9a, respectively, were hydrolyzed very
quickly, yet unselectively (Table 1). In addition, lipase PS
did not accept the pivalic acid oxime ester (±)-10a. Further
experiments showed that acetic acid oxime ester (±)-7a and
butyrylated oxime ester (±)-11a were good substrates and
the products were obtained with high enantiomeric excess
(Table 1).
In polar solvents such as acetonitrile or acetone, only low
ee-values were obtained. High ee-values were observed using
© 2002 NRC Canada

688
Can. J. Chem. Vol. 80, 2002
Table 2. Results of lipase-catalyzed transesterification of (±)-11a–f.
Oxime ester
[a]2D0 (c)a
Oxime
[a]2D0 (c)a
Reaction
time (h)
Substrate
R/n
ee/yield (%)b
ee/yield (%)b
–0.9 (1.4)
+14.6 (1.1)
+8.6 (0.9)
+21.5 (0.72)
+22.1 (1.2)
+107.2 (1.2)
+165.5 (1.8)
91
70
120
145
70
a
b
c
d
e
f
-CH2CH=CH2/1
-CH3/1
-(CH2)2CH=CH2/1
-(CH2)4CH=CH/1
-CH2CH=CH2/2
-CH3/2
96/85
57/75
93/83
96/87
97/92
96/87
92/85
33/119
89/90
95/89
89/96
95/78
–4.3 (0.7)
–11.8 (1.0)
–12.6 (0.9)
–116.6 (0.87)
–106.8 (1.6)
100
aIn CHCl3.
bIsolated yields, calculated for 100% (R)- and (S)-enantiomer.
Scheme 4.
Scheme 5.
Fig. 1. Structures of histrionicotoxin and perhydro histrionicotoxin.
from skin extracts of the neotropical frog Dendrobates
histrionicus. These spirocyclic alkaloids influence neurophy-
siological ion transport and their action on the acetylcholine
receptor is of considerable biological interest (8). The total
synthesis of racemic perhydro histrionicotoxin 13 was
achieved by Kishi et al. (9a) and Corey et al. (9b); however,
the total synthesis of enantiomerically pure histrionicotoxin
was achieved only recently by an ingenious route reported
by Stork and Zhao (10a).
Our route towards the enantiomerically pure spirocyclic
framework is related to the methodology reported by Witkop
and Kiessing (11) (Scheme 5). In this synthesis, the key step
towards the spirocyclic framework is a Dieckmann reaction.
To obtain suitable starting materials for this step, we chose
to elaborate the enantiomerically pure oxime (+)-1d. The
corresponding tosylate (+)-14 was synthesized quantitatively
by using tosyl chloride in pyridine. Rearrangement took
place while stirring the tosylate in the presence of silica gel.
Lactam (–)-15 was isolated in 78% yield as the only regio-
and stereoisomer. It is well known that the Beckmann rear-
rangement occurs with retention of the configuration at a mi-
grating stereogenic center, and indeed, NMR experiments
employing Eu(hfc)3 proved that no racemization had taken
place. (The racemic lactam (±)-15 exhibits two triplets for
the methyl group of the ethyl ester moiety at 1.32 and
1.64 ppm, whereas the homochiral lactam (–)-15 shows only
one triplet at 1.26 ppm (12).)
toluene and hexane, but prolonged reaction times (up to 20
d) were required for good conversion. We achieved the best
results by using ethers as solvents; amongst the ones
screened, diisopropyl ether proved to be most suitable for
our purposes in terms of reaction times and selectivity.
Based on these initial results, we synthesized racemic
butyrylated oxime esters (±)-11a–f (Scheme 4, Table 2). Ki-
netic resolution of these substrates was achieved over 3–5
days. Thus, stirring the oxime esters in diisopropyl ether
with lipase PS in the presence of n-butanol gave rise to
highly stereoselective saponifications of the substrates. No
striking difference was observed on starting from cyclopen-
tane (11a–d) or cyclohexane derivatives (11e, f). Similarly,
the size of the alkyl side chain at the quaternary carbon cen-
ter does not play a major role in stereodifferentiation. All
products were isolated in high yields with good ee-values af-
ter column chromatography. The butyrylated oxime esters
(–)-11a–f were saponified quantitatively in 10 min by stir-
ring with potassium carbonate in methanol. The ester moiety
at the quaternary center remains intact during the two-step
procedure (kinetic resolution and hydrolysis).
Synthesis of the spirocyclic framework of histrionico-
toxin (–)-3
Histrionicotoxin 12 and their hydrogenated congeners 13
(Fig. 1) are well-known neurotoxins used by natives of
South America as arrow poisons. They have been isolated
Ozonolysis of the double bond was carried out as de-
scribed by Marshall et al. (13). Reaction with solid NaOH in
© 2002 NRC Canada

Diedrichs et al.
689
ethanol at –78°C provided the diester (–)-16 in 88% yield.
Subsequently, a Dieckmann reaction was carried out in the
presence of potassium tert-butylate, affording the spirocycle
17 as a crystalline product. Without further characterization,
saponification and decarboxylation was carried out leading
to (–)-3 in 68% yield (from 16). Because racemic ketone
(±)-3 was used to synthesize perhydro histrionicotoxin, this
synthesis represents a formal total asymmetric synthesis of
this alkaloid (9). Currently we are exploring the synthesis of
histrionicotoxin.
chloromethane–methanol (95:5) or distillation, the desired
products were obtained in 81–94% yield.
General procedure for kinetic resolution of oxime esters
(±)-11a–f
Lipase PS (500 mg) and n-butanol (5 mL) were added to a
solution of (±)-11 (2 mmol) in diisopropyl ether (15 mL).
The reaction was monitored by HPLC. After the reaction,
the enzyme was filtered through Celite™ and washed with
diethyl ether. The crude residue was subjected to column
chromatography using dichloromethane–methanol (98:2) as
the eluent.
Conclusions
We have demonstrated that oxime esters are valuable sub-
strates for kinetic resolution with lipases. Transesterification
of the butyrylated oximes gave products containing a quater-
nary stereocenter adjacent to the oxime functionality; this
method is therefore a valuable tool to provide building
blocks with this structural feature. The configuration at the
stereocenter could be unambigously determined by chemical
correlation, which is based on the synthesis of known natu-
ral products.
The oximes were employed in Beckmann rearrangements
leading to enantiomerically pure lactams. These lactams can
be used for the synthesis of non-natural amino acids and for
the preparation of spirocyclic alkaloids as demonstrated in
the case of perhydro histrionicotoxin.
General procedure for saponification of oxime esters
(–)-11a–f
To a saturated solution of K2CO3 in methanol (20 mL)
was added oxime ester (±)-11 (1 mmol) and the solution was
stirred for 10 min. After evaporation to dryness, the residue
was dissolved in water (45 mL). The aqueous layer was ex-
tracted with diethyl ether (3 × 50 mL). The combined or-
ganic layers were washed with 5% hydrochloric acid
(10 mL) and saturated brine. After drying over MgSO4, fil-
tration and evaporation of the solvent gave the oximes (–)-1
in quantitative yield.
Ethyl 1-allyl-2-[(butyryloxy)imino]cyclopentane
carboxylate (11a)
3
1H NMR (CDCl3) d: 0.94 (t, J = 7.3 Hz, 3H, CH3), 1.21
3
3
(t, J = 7.1 Hz, 3H, CH3), 1.66 (q, J = 7.4 Hz, 2H, CH2),
1.76–1.90 (m, 3H, CH2), 2.15–2.83 (m, 7H, CH2), 4.13 (q,
3J = 7.1 Hz, 2H, OCH2), 5.02–5.11 (m, 2H, =CH2), 5.67–
5.87 (m, 1H, =CH). 13C NMR (CDCl3) d: 14.2, 14.5, 18.8,
22.0, 29.9, 35.2, 39.9, 57.3, 61.9, 72.8, 119.4, 133.9, 171.7,
172.9, 174.2. EI-HRMS calcd. for C15H23NO4: 281.1627;
found: 281.1625.
Experimental
All reagents were of commercial quality. Lipases were
purchased from Fluka (Switzerland) and were provided by
Amano (Japan). All solvents were distilled prior to use. Sil-
ica gel 60 F254 plates from Merck (Germany) were used for
TLC. Column chromatography was performed using silica
gel 60/230–400 mesh from Merck. NMR spectra were mea-
sured on a Bruker ARX 200 spectrometer (1H 200 MHz and
13C 50 MHz). IR spectra were measured on an FT-IR spec-
trometer NICOLET 510 P. Mass spectra were obtained with
a FINNIGAN MAT 8430. The optical rotations were re-
corded on a PerkinElmer 241 polarimeter. For HPLC a
Merck-Hitachi chromatograph equipped with an OB-H col-
umn from Daicel Chemical Industries (25 × 0.46 cm) was
used. For GLC measurements an HP 8890 gas chromato-
graph with a Lipodex E cyclodextrin column (12.5 m,
Macherey & Nagel, Germany) was used. Elemental analyses
were carried out on a PerkinElmer analytical analyzer 241.
Ethyl 1-methyl-2-[(butyryloxy)imino]cyclopentane
carboxylate (11b)
3
1H NMR (CDCl3) d: 1.00 (t, J = 7.3 Hz, 3H, CH3), 1.26
3
(t, J = 7.1 Hz, 3H, CH3), 1.29 (s, 3H, CH3) 1.63–2.02 (m,
5H, CH23), 2.19–2.45 (m, 3H, CH2), 2.58–2.76 (m, 2H, CH2),
4.19 (q, J = 7.1 Hz, 2H, OCH2). 13C NMR (CDCl3) d: 14.1,
14.5, 18.8, 21.9, 22.0, 29.7, 35.2, 39.4, 53.6, 61.8, 171.6,
174.0, 175.5. EI-HRMS calcd. for C13H21NO4: 295.1471;
found: 295.1488.
Ethyl 1-(but-3-enyl)-2-[(butyryloxy)imino]cyclopentane
carboxylate (11c)
3
1H NMR (CDCl3) d: 0.99 (t, J = 7.4 Hz, 3H, CH3), 1.26
General procedure for the preparation of racemic
oxime esters (±)-11a–f
3
3
(t, J = 7.1 Hz, 3H, CH3), 1.71 (q, J = 7.4 Hz, 2H, CH2),
3
To a solution of oxime (±)-1 (5.0 mmol) in dry pyridine
(25 mL), was added dropwise butyric acid chloride
(5.0 mmol) over a period of 10 min at 0°C under an argon
atmosphere. The reaction mixture was stirred for 1 h at this
temperature and an additional 3 h at room temperature. After
adding 5% hydrochloric acid (30 mL) the aqueous layer was
extracted with diethyl ether (3 × 70 mL). The combined or-
ganic layers were washed with 10% hydrochloric acid
(10 mL), saturated sodium bicarbonate solution (2 × 40 mL),
and finally with saturated brine. The organic layer was dried
over MgSO4, filtered, and evaporated to dryness under re-
duced pressure. After column chromatography with di-
1.78–2.81 (m, 12H, CH2), 4.19 (q, J = 7.1 Hz, 2H, OCH2),
4.92–5.06 (m, 2H, =CH2), 5.70–5.90 (m, 1H, =CH).
13C NMR (CDCl3) d: 14.1, 14.4, 18.7, 22.0, 27.8, 29.8, 34.9,
36.2, 37.5, 57.7, 61.9, 115.2, 138.2, 172.0, 172.9, 174.5. EI-
HRMS calcd. for C16H25NO4: 295.1784; found: 295.1790.
Ethyl 1-(hex-5-enyl)-2-[(butyryloxy)imino]cyclopentane
carboxylate (11d)
3
1H NMR (CDCl3) d: 1.02 (t, J = 7.4 Hz, 3H, CH3), 1.24
3
3
(t, J = 7.1 Hz, 3H, CH3), 1.62 (q, J = 7.4 Hz, 2H, CH2),
3
1.68–2.73 (m, 16H, CH2), 4.17 (q, J = 7.1 Hz, 2H, OCH2),
4.76–4.98 (m, 2H, =CH2), 5.56–5.78 (m, 1H, =CH).
© 2002 NRC Canada

690
Can. J. Chem. Vol. 80, 2002
13C NMR (CDCl3) d: 14.0, 14.4, 18.3, 21.7, 24.6, 27.3, 29.1,
33.4, 34.6, 36.5, 37.8, 54.5, 61.1, 114.4, 138.7, 172.6, 173.1,
174.8. EI-HRMS calcd. for C18H29NO4: 323.2097; found:
323.2110.
for C9H15NO3 (185.22): C 58.36, H 8.16, N 7.56; found:
C 58.18, H 8.34, N 7.80.
Ethyl 1-(3-butenyl)-2-(hydroxyimino)cyclopentane
carboxylate (1c)
3
1H NMR (CDCl3) d: 1.26 (t, J = 7.1 Hz, 3H, CH3), 1.63–
Ethyl 1-allyl-2-[(butyryloxy)imino]cyclohexane
carboxylate (11e)
3
2.69 (m, 10H, CH2), 4.15 (q, J = 7.1 Hz, 2H, OCH2), 4.88–
3
1H NMR (CDCl3) d: 1.00 (t, J = 7.3 Hz, 3H, CH3), 1.25
5.09 (m, 2H, =CH2), 5.65–5.88 (m, 1H, =CH), 9.54 (s, 1H,
OH). 13C NMR (CDCl3) d: 14.4, 22.2, 27.7, 30.0, 35.1, 36.3,
56.6, 61.7, 115.2, 138.3, 166.0, 173.3. EI-HRMS calcd. for
C12H19NO3: 225.136; found: 225.1379.
3
(t, J = 7.1 Hz, 3H, CH3), 1.35–1.98 (m, 8H, CH2), 2.09–
3
2.83 (m, 5H, CH2), 3.18–3.28 (m, 1H, CH2), 4.17 (q, J =
7.1 Hz, 2H, OCH2), 5.01–5.09 (m, 2H, =CH2), 5.81–6.02
(m, 1H, =CH). 13C NMR (CDCl3) d: 14.1, 14.6, 18.7, 23.0,
26.2, 26.3, 35.3, 36.2, 40.5, 55.1, 61.6, 118.6, 134.0, 167.5,
172.0, 172.7. EI-HRMS calcd. for C16H25NO4: 295.1784;
found: 295.1792.
Ethyl 1-(5-hexenyl)-2-(hydroxyimino)cyclopentane
carboxylate (1d)
3
1H NMR (CDCl3) d: 1.32 (t, J = 7.1 Hz, 3H, CH3), 1.54–
3
2.79 (m, 14H, CH2), 4.22 (q, J = 7.1 Hz, 2H, OCH2), 4.92–
Ethyl 2-[(butyryloxy)imino]-1-methylcyclohexane
carboxylate (11f)
5.12 (m, 2H, =CH2), 5.65–5.88 (m, 1H, =CH), 9.28 (s, 1H,
OH). 13C NMR (CDCl3) d: 14.0, 21.7, 24.6, 27.3, 29.1, 33.4,
34.6, 36.5, 54.5, 61.1, 114.4, 138.7, 165.9, 173.1. Anal.
calcd. for C14H23NO3 (253.17): C 66.36, H 9.16, N 5.53;
found: C 66.03, H 9.33, N 5.82.
3
1H NMR (CDCl3) d: 0.98 (t, J = 7.3 Hz, 3H, CH3), 1.25
3
(t, J = 7.1 Hz, 3H, CH3), 1.31–1.41 (m, 2H, CH2), 1.45 (s,
3H, CH3), 1.52–2.02 (m, 6H, CH2), 2.39–2.46 (m, 3H, CH2),
3
3.19–3.28 (m, 1H, CH2), 4.17 (q, J = 7.1 Hz, 2H, OCH2).
13C NMR (CDCl3) d: 14.1, 14.5, 18.7, 22.9, 23.1, 25.9, 26.1,
35.3, 38.6, 51.2, 61.6, 168.5, 172.0, 174.3. EI-HRMS calcd.
for C14H23NO4: 269.1627; found: 269.1681.
Ethyl 1-allyl-2-(hydroxyimino)cyclohexane carboxylate (1e)
3
1H NMR (CDCl3) d: 1.26 (t, J = 7.1 Hz, 3H, CH3), 1.34–
1.98 (m, 6H, CH2), 2.33–2.48 (m, 2H, CH2), 2.66–2.76 (m,
1H, CH2), 3.17–3.24 (m, 1H, CH2), 4.18 (q, 3J = 7.1 Hz, 2H,
OCH2), 5.02–5.08 (m, 2H, =CH2), 5.71–5.91 (m, 1H, =CH),
9.21 (s, 1H, OH). 13C NMR (CDCl3) d: 14.6, 22.9, 23.6,
25.9, 35.5, 40.1, 54.0, 61.4, 118.6, 133.9, 160.4, 173.4. EI-
HRMS calcd. for C12H19NO3: 225.1365; found: 225.1370.
Ethyl 2-[(acetyloxy)imino]-1-allylcyclopentane carboxylate
(7a)
1
[a]2D0 –2.0 (c 1.0, CHCl3, ee > 98%). H NMR (CDCl3) d:
3
1.23 (t, J = 7.1 Hz, 3H, CH3), 1.73–1.91 (m, 3H, CH2),
3
2.04–2.83 (m, 5H, CH2), 2.16 (s, 3H, CH3), 4.16 (q, J =
7.1 Hz, 2H, OCH2), 5.04–5.13 (m, 2H, =CH2), 5.66–5.85
(m, 1H, =CH). 13C NMR (CDCl3) d: 14.5, 20.2, 22.0, 29.9,
35.2, 39.8, 57.2, 61.9, 119.4, 133.8, 169.5, 172.8, 174.1. EI-
HRMS calcd. for C13H19NO4: 253.1314; found: 253.1288.
Ethyl 2-(hydroxyimino)-1-methylcyclohexane carboxylate
(1f)
1
3
mp 64.7°C. H NMR (CDCl3) d: 1.29 (t, J = 7.1 Hz, 3H,
CH3), 1.39 (s, CH3, 3H), 1.55–2.70 (m, 8H, CH2), 4.15 (q,
3J = 7.1 Hz, 2H, OCH2), 8.25 (br s, 1H, OH). 13C NMR
(CDCl3) d: 14.6, 23.0, 23.3, 23.4, 25.9, 38.4, 50.4, 61.5,
161.1, 175.0. Anal. calcd. for C10H17NO3 (253.17): C 60.28,
H 8.60, N 7.03; found: C 60.13, H 8.72, N 7.12.
Ethyl 1-allyl-2-{[(2,2-dimethylpropanoyl)oxy]imino}cyclo-
pentane carboxylate (10a)
1H NMR (CDCl3) d: 1.22 (s, 9H, CH3), 1.26 (t, 3J =
7.1 Hz, 3H, CH3), 1.14–1.26 (m, 2H, CH2), 1.77–1.87 (m,
2H, CH2), 2.23–2.79 (m, 4H, CH2), 4.08–4.20 (m, 2H,
OCH2), 5.02–5.11 (m, 2H, =CH2), 5.73–5.82 (m, 1H, =CH).
13C NMR (CDCl3) d: 14.5, 21.9, 27.6, 29.7, 35.1, 39.8, 57.3,
61.9, 119.3, 133.9, 169.0, 172.7, 175.2 (one quaternary cen-
ter could not be determined). EI-HRMS calcd. for C16H25NO4:
295.1784; found: 295.1812.
Ethyl 1-(5-hexenyl)-2-([tosyloxy]imino)cyclopentane
carboxylate ((+)-14)
Oxime (+)-1d (0.30 g, 1,2 mmol) was dissolved in
pyridine (2.0 mL) and p-toluene sulfonic acid (0.23 g, 1.2 mmol)
was added. The solution was stirred for 20 h at room tem-
perature. After addition of NaHCO3 (5 mL of a 5% solu-
tion), the reaction mixture was extracted with CH2Cl2 (3 ×
20 mL). The combined organic extracts were washed with
5% NaHCO3, water, and brine, dried over MgSO4, filtered
and the organic solvent evaporated under reduced pressure to
furnish an oily residue (0.42 g, 87%). Further purification
Ethyl 1-allyl-2-(hydroxyimino)cyclopentane carboxylate (1a)
3
1H NMR (CDCl3) d: 1.21 (t, J = 7.1 Hz, 3H, CH3), 1.67–
3
1.93 (m, 3H, CH2), 2.19–2.80 (m, 5H, CH2), 4.12 (q, J =
7.1 Hz, 2H, OCH2), 5.00–5.09 (m, 2H, =CH2), 5.63–5.84
(m, 1H, =CH). 13C NMR (CDCl3) d: 14.4, 22.1, 27.9, 34.5,
41.1, 56.3, 61.7, 118.9, 134.0, 165.8, 173.2. EI-HRMS
calcd. for C11H17NO3: 211.1208; found: 211.1207.
1
was not required. [a]2D0 +16.8 (c 1.33, CHCl3). H NMR
(CDCl3) d: 1.22 (t, 3J = 7.1 Hz, 3H, CH3), 1.25–2.40 (m, 12H,
3
CH2), 2.51 (s, 3H, CH3), 2.70 (m, 2H, CH2), 4.13 (q, J =
Ethyl 2-(hydroxyimino)-1-methylcyclopentane carboxylate
(1b)
7.1 Hz, 2H, OCH2), 5.05 (m, 2H, CH2=), 5.84 (m, 1H,
CH=), 7.38 (m, 2H, Ar-H), 7.93 (m, 2H, Ar-H). 13C NMR
(CDCl3) d: 13.9, 21.5, 21.6, 24.3, 29.1, 29.5, 33.4, 35.0,
35.6, 57.9, 61.3, 114.4, 128.9, 129.3, 133.0, 138.6, 144.6,
172.1, 174.9. Anal. calcd. for C14H29NO3S (407.18): C 61.89,
H 7.18, N 3.44; found: C 61.69, H 7.40, N 3.79.
3
1H NMR (CDCl3) d: 1.27 (t, J = 7.1 Hz, 3H, CH3), 1.43
3
(s, CH3, 3H), 1.62–2.65 (m, 6H, CH2), 4.17 (q, J = 7.1 Hz,
2H, OCH2), 9.10 (br s, 1H, OH). 13C NMR (CDCl3) d: 14.5,
22.1, 22.8, 27.6, 38.6, 52.6, 61.6, 167.5, 174.6. Anal. calcd.
© 2002 NRC Canada

Diedrichs et al.
691
6.60 (s, 1H, NH). 13C NMR (CDCl3) d: 23.0, 24.7, 26.2,
35.3, 35.6, 35.7, 36.5, 66.3, 174.4, 211.3. Anal. calcd. for
C10H15NO2 (181.23): C 66.27, H 8.34, N 7.73; found: C 66.12,
H 8.76, N 7.72.
R-(–)-Ethyl 2-(hex-5-enyl)-6-oxo-piperidine-2-carboxylate
((–)-15)
Tosyloxime 14 (0.20 g, 0.49 mmol) was dissolved in
CH2Cl2 (15 mL) and silica gel (10 g) was added. The reac-
tion slurry was stirred for 16 h, after which TLC control
showed no starting material. The silica gel was filtered off
and washed several times with a methanol–CH2Cl2 mixture.
Residual toluene sulfonic acid was removed by washing with
water, if necessary. The combined organic extracts were
dried over MgSO4, filtered, and evaporated under reduced
pressure to afford slightly yellow crystals (0.97 g, 78%); mp
Acknowledgments
N. Diedrichs and I. Gedrath would like to thank the Fonds
der Chemischen Industrie for a doctoral scholarship. R.
Krelaus has been awarded the Graduiertenförderung, for
which he is very grateful. The work has been supported by
the Fonds der Chemischen Industrie and by gifts from
Amano.
1
46.6°C. [a]2D0 –8.83 (c 1.22, CHCl3). H NMR (CDCl3) d:
3
1.26 (t, J = 7.1 Hz, 3H, CH3), 1.32–2.46 (m, 14H, CH2),
3
4.18 (q, J = 7.1 Hz, 2H, OCH2), 4.82 (m, 2H, CH2=), 5.78
(m, 1H, CH=), 6.13 (s, 1H, NH). 13C NMR (CDCl3) d: 14.0,
17.8, 22.5, 28.5, 30.4, 30.8, 3.1, 40.0, 61.6, 62.7, 114.7,
138.0, 171.5, 173.1. Anal. calcd. for C14H23NO3 (253.17):
C 66.36, H 9.16, N 5.53; found: C 66.12, H 9.13, N 5.72.
References
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R-(–)-Ethyl 2-(5-ethoxy-5-oxopentyl)-6-oxo-piperidine-2-
carboxylate ((–)-16)
Ozone was passed through a mixture of lactam 15 (0.12 g,
0.47 mmol) dissolved in CH2Cl2 (4 mL) and ethanolic
NaOH (2.5 mL, 2.5 M) at –78°C. This process was stopped
when the characteristic blue color appeared. The reaction
mixture was warmed to room temperature and diluted with
water and ether. The organic layer was separated and the
aqueous phase was extracted with ether (3 × 50 mL). The
combined organic extracts were dried over MgSO4, filtered,
and the organic solvent was evaporated under reduced pres-
sure to afford a colorless oil (0.13 g, 88%), which was ana-
1
lytically pure. [a]D20 –6.60 (c 2.0, CHCl3). H NMR (CDCl3)
3
3
d: 1.22 (t, J = 7.1 Hz, 3H, CH3), 1.26 (t, J = 7.1 Hz, 3H,
3
CH3), 1.50–2.30 (m. 14H, CH2), 4.09 (q, J = 7.1 Hz, 2H,
3
OCH2), 4.18 (q, J = 7.1 Hz, 2H, OCH2), 6.30 (s, 1H, NH).
13C NMR (CDCl3) d: 13.9, 14.0, 17.7, 22.7, 24.6, 30.2, 30.7,
33.7, 39.4, 60.1, 61.6, 62.5, 171.8, 172.8, 173.0. Anal. calcd.
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C 60.32, H 8.11, N 4.71.
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(–)-1-Azaspiro[5.5]undecane-2,7-dione ((–)-3)
To potassium tert-butoxide (0.17 g, 1.6 mmol) dissolved
in pyridine (3 mL) under an argon atmosphere was added
dropwise diester 16 (0.20 g, 0.7 mmol) in pyridine (3 mL).
The reaction mixture was stirred for 2 h at 20°C. Diluted
HCl was added and then brine (10 mL) was added. After ex-
traction with ethyl acetate (3 × 40 mL), the combined or-
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NaHCO3, and brine, and then dried over MgSO4, filtered,
and evaporated. The remaining oily residue (0.12 g, 75%)
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and was filtered off, dried over P2O5 (67 mg, 75%), and used
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1
CHCl3). H NMR (CDCl3) d: 1.58–2.68 (m, 14H, 7 × CH2),
© 2002 NRC Canada